Granulation of active pharmaceutical ingredients

Abstract

The present invention discloses a dry formulation or granulation comprising, in admixture, more than 50 wt. % of active pharmaceutical ingredient and from 1 to 10 wt. % of each of any nonaqueous excipient selected from liquid substances. In a preferred embodiment no water or lower alcohol has been added in any step of the preparation of the dry formulation or granulation, and the nonaqueous excipient selected from liquid substances is adsorbed to dryness by the active pharmaceutical ingredient and/or by a further solid excipient. Pharmaceutical formulations based on such dry formulation or granulation, and processes for the preparation thereof, are described as well. The dry formulations or granulations reliably and effectively further processed under dry conditions without requiring active drying, including e.g. briquetting, slugging, sieving, milling, tabletting, further fine granulating, direct compression, and the like.

1 . A dry formulation or granulation comprising, in admixture, more than 50 wt. % of an active pharmaceutical ingredient and from 1 to 10 wt. % of each of any nonaqueous excipient selected from liquid substances. 
     
     
         2 . A dry formulation or granulation comprising, in admixture and without water or lower alcohol having been added in any step of its preparation, (i) more than 50 wt. % of an active pharmaceutical ingredient and (ii) a nonaqueous excipient selected from liquid substances; wherein the liquid nonaqueous excipient is adsorbed to dryness by the active pharmaceutical ingredient and/or by a further solid excipient. 
     
     
         3 . The dry formulation or granulation according to  claim 1  or  2 , wherein the nonaqueous excipient is selected from the group consisting of liquid surfactants; liquid polyethylene glycol; liquid paraffin; propylene glycol; liquid fatty alcohols with at least 8 carbon atoms; liquid triglycerides or oils; liquid wax; liquid polyethoxylated fatty acids; liquid PEG glycerol fatty acid esters; and liquid ethers of polyethylene glycol and alkyl alcohols. 
     
     
         4 . The dry formulation or granulation according to  claim 1 , further comprising a solid excipient adsorbing the originally liquid nonaqueous excipient. 
     
     
         5 . The dry formulation or granulation according to  claim 1 , wherein no water, aqueous solution, lower alcohol or lower alcoholic solution has been added to the dry formulation during its preparation. 
     
     
         6 . The dry formulation or granulation according to  claim 1 , further comprising a solid excipient selected from the group consisting of microcrystalline cellulose, lactose, isomalt, solid polyethylene glycol, mannitol, sorbitol, starch, calcium phosphates, carboxymethylcellulose (calcium or sodium), cellulose, silicified microcrystalline cellulose, cellulose acetate, colloidal silicon dioxide, dextrines, dextrin, glucose, ethylcellulose, fructose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose, lactitol, magnesium carbonate, maltodextrin, maltose, methylcellulose, polydextrose, pregelatinized starch, zein, and calcium silicate. 
     
     
         7 . The dry formulation or granulation according  claim 1 , wherein the nonaqueous, liquid excipient is mixed with a solid excipient at a weight ratio of 1:10 to 10:1. 
     
     
         8 . The dry formulation or granulation according to  claim 1 , wherein the active pharmaceutical ingredient has a solubility at pH of 2 below 0.1 mg/ml. 
     
     
         9 . The dry formulation or granulation according to  claim 1 , wherein active pharmaceutical ingredient is selected from the group consisting of eprosartan, irbesartan, amoxiciline, levofloxacine, metformin and sevelamer, their salts, hydrates and solvates, wherein said active pharmaceutical ingredient is optionally combined with another active pharmaceutical ingredient. 
     
     
         10 . A process for the preparation of a pharmaceutical formulation, comprising mixing more than 50 wt. % of an active pharmaceutical ingredient with from 1 to 10 wt. % of each of any nonaqueous liquid excipient to obtain a dry or moisture-activated formulation, and subjecting the thus obtained formulation to processing to prepare the pharmaceutical formulation. 
     
     
         11 . The dry formulation or granulation according to  claim 2 , wherein the nonaqueous excipient is present in a total amount of from 1 to 10 wt. %. 
     
     
         12 . A process for the preparation of a pharmaceutical formulation, comprising subjecting an active pharmaceutical ingredient to granulation with a nonaqueous liquid excipient, without adding any one of water, an aqueous solution, lower alcohol or lower alcoholic solution, as granulation liquid, wherein the nonaqueous liquid excipient and other optional excipients each has a water activity of less than 0.62 determined at room temperature. 
     
     
         13 . The process according to  claim 10  or  claim 12 , wherein the nonaqueous excipient is selected from surfactants; liquid polyethylene glycol; liquid paraffin; propylene glycol; liquid fatty alcohols with at least 8 carbon atoms; liquid triglycerides or oils; liquid wax; liquid polyethoxylated fatty acids; liquid PEG glycerol fatty acid esters; and ethers of polyethylene glycol and alkyl alcohols; alone or together with other pharmaceutically acceptable excipients. 
     
     
         14 . The process according to  claim 10  or  claim 12 , further comprising admixing with a solid excipient capable adsorbing the liquid nonaqueous excipient, and optionally admixing with other solid pharmaceutically acceptable excipients; wherein the solid excipient capable adsorbing the liquid nonaqueous excipient is preferably selected from the group consisting of microcrystalline cellulose, lactose, isomalt, solid polyethylene glycol, mannitol, sorbitol, starch, calcium phosphates, carboxymethylcellulose (calcium or sodium), cellulose, silicified microcrystalline cellulose, cellulose acetate, colloidal silicon dioxide, dextranes, dextrin, glucose, ethylcellulose, fructose, hydroxyethyl cellulose, hydroxyethylmethyl cellulose, hydroxypropyl cellulose, hypromellose, lactitol, magnesium carbonate, maltodextrin, maltose, methylcellulose, polydextrose, pregelatinized starch, zein, and calcium silicate. 
     
     
         15 . The process according to  claim 10  or  claim 12 , wherein the active pharmaceutical ingredient has a property of existing in at least two polymorphic forms, while the form subjected to granulation is provided in a single first form, whereupon an interconversion from said first form to another or mixed form of the active pharmaceutical ingredient is prevented during granulation, also during the optional steps of briquetting or slugging, sieving or milling, and tabletting. 
     
     
         16 . The process according to  claim 15 , further comprising direct compression or dry granulation, and optionally further comprising tabletting. 
     
     
         17 . The process according to  claim 10  or  claim 12 , wherein said active pharmaceutical ingredient is selected from a group consisting of eprosartan, irbesartan, amoxiciline, levofloxacine, metformin and sevelamer, their salts, hydrates or solvates, wherein said active pharmaceutical ingredient is optionally combined with another active pharmaceutical ingredient. 
     
     
         18 . A pharmaceutical formulation, comprising a dry formulation or granulation according to  claim 1  or  claim 2 . 
     
     
         19 . The pharmaceutical formulation according to  claim 18 , which is a tablet, wherein the tablet has a hardness of between 40 and 180 N. 
     
     
         20 . (canceled) 
     
     
         21 . A pharmaceutical formulation, comprising a dry formulation or granulation obtained by a process according to  claims 10 .